Trace amines are biogenic non-catecholamine monoamines that are present at low concentrations in the vertebrate nervous system. Some trace amines, such as octopamine and tyramine, are more abundant in invertebrate nervous systems, where their function as neurotransmitters is fairly well established. The heterogeneous CNS distribution and rapid turnover of trace amines, together with the existence of trace amine receptors, suggest that some trace amines may also be neurotransmitters or co-transmitters in the mammalian CNS. This proposal takes advantage of the recent identification and molecular cloning of the DNA for a family of trace amine receptors (TARs). Interestingly, the TARs are clustered in a region of human chromosome 6 (6q23) where linkage to schizophrenia has been suggested by a number of studies. A role for trace amines in neuropsychiatric disorders has been proposed, and the TARS are also sites of action for many abused drugs. These findings suggest the hypothesis that a polymorphism in one of the TARs changes the function of the protein and thus contributes to the symptoms of schizophrenia and/or to drug abuse. As an initial step towards evaluating this hypothesis we propose the following specific aims: 1. Each TAR will be stably expressed in mammalian cells under conditions that promote its expression on the cell surface. Three strategies to be tested are genetic modification of the receptors, the use of potential ligands as "pharmacological chaperones", and inhibition of receptor internalization. 2. Agonists and antagonists for the TARs will be identified by testing the ability of potential monoamine ligands to stimulate or inhibit cyclic AMP accumulation and to activate mitogen-activated protein kinases in mammalian cells stably expressing the receptor subtypes. 3. TAR variants with non-synonymous SNPs will be stably expressed in mammalian cells to determine the effect of the polymorphism on cell surface expression, ligand binding, and function of the receptor. The ideal outcome of these studies would be to identify conditions under which all TARs encoding full-length receptors are expressed on the cell surface, to identify agonists and antagonists for each TAR subtype, and to identify allelic variants that alter the function or ligand binding of a TAR subtype